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Although nanoparticle-based lymphatic drug delivery systems promise better treatment of cancer, infectious disease, and immune disease, their clinical translations are limited by low delivery efficiencies and unclear transport mechanisms. Here, we employed a three-dimensional (3D) lymphatics-on-a-chip featuring an engineered lymphatic vessel (LV) capable of draining interstitial fluids including nanoparticles. We tested lymphatic drainage of different sizes (30, 50, and 70 nm) of PLGA-b-PEG nanoparticles (NPs) using the lymphatics-on-a-chip device. In this study, we discovered that smaller NPs (30 and 50 nm) transported faster than larger NPs (70 nm) through the interstitial space, as expected, but the smaller NPs were captured by lymphatic endothelial cells (LECs) and accumulated within their cytosol, delaying NP transport into the lymphatic lumen, which was not observed in larger NPs. To examine the mechanisms of size-dependent NP transports, we employed four inhibitors, dynasore, nystatin, amiloride, and adrenomedullin, to selectively block dynamin-, caveolin-, macropinocytosis-mediated endocytosis-, and cell junction-mediated paracellular transport. Inhibiting dynamin using dynasore enhanced the transport of smaller NPs (30 and 50 nm) into the lymphatic lumen, minimizing cytosolic accumulation, but showed no effect on larger NP transport. Interestingly, the inhibition of caveolin by nystatin decreased the lymphatic transport of larger NPs without affecting the smaller NP transport, indicating distinct endocytosis mechanisms used by different sizes of NPs. Macropinocytosis inhibition by amiloride did not change the drainage of all sizes of NPs; however, paracellular transport inhibition by adrenomedullin blocked the lymphatic transport of NPs of all sizes. We further revealed that smaller NPs were captured in the Rab7-positive late-stage lymphatic endosomes to delay their lymphatic drainage, which was reversed by dynamin inhibition, suggesting that Rab7 is a potential target to enhance the lymphatic delivery of smaller NPs. Together, our 3D lymphatics-on-a-chip model unveils size-dependent NP transport mechanisms in lymphatic drug delivery.
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INTRODUCTION: Currently, there is no mandatory standard for reporting race and ethnicity in medical journals, presenting significant barriers to studying disparities in medical outcomes. We seek to investigate whether greater recent awareness of diversity and inclusion reflects in reporting of race and ethnicity by peer-reviewed cardiothoracic articles. METHODS: Pubmed was queried for clinical outcomes articles published from January 2017 to June 2023 in the Journal of Thoracic and Cardiovascular Surgery, Annals of Thoracic Surgery, Journal of Heart and Lung Transplantation, and CHEST Journal. Basic science, translational studies, and international studies were excluded. SAS Studio was used for statistical analysis. RESULTS: 817 papers were reviewed, 378 reported race/ethnicity with 354 (93%) reporting White, 267 (71%) reporting Black, 128 (34%) reporting Hispanic, and 119 (31%) reporting Asian. Over 8-y, there were no statistically significant changes in percent of articles that included White (odds ratio 0.808 95% confidence interval [0.624-1.047], P = 0.1068), Black (1.125 [0.984-1.288], P = 0.0857), or Asian (1.096 [0.960-1.250], P = 0.1751) groups. Hispanics were more likely to be reported in recent years (1.147 [1.006-1.307], P = 0.0397). Subset analysis was performed on cardiac (n = 157) and thoracic articles (n = 157) with no significant trends for race reporting in these subsets. CONCLUSIONS: Minorities remain underrepresented in reported patient populations in peer-reviewed cardiothoracic journals. Future efforts should prioritize accurately representing these populations in the literature. Inaccurate data and exclusion of minority populations can contribute to disparities observed in overall outcomes.
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PURPOSE: There is a lack of systematic solutions to manage supportive care issues in racial/ethnic minorities (REM) receiving treatment for cancer. We developed and implemented an electronic patient-reported outcome (ePRO)-driven symptom management tool led by oncology pharmacists in a majority-minority cancer center located in Southern California. This study was designed to evaluate the implementation outcomes of our multilevel intervention. METHODS: This was a prospective, pragmatic, implementation study conducted between July 2021 and June 2023. Newly diagnosed adult patients with cancer receiving intravenous anticancer therapies completed symptom screening using ePRO that consists of the Patient-Reported Outcomes Measurement Information System measures at each infusion visit during the study. ePRO results were presented to an oncologist pharmacist for personalized symptom management and treatment counseling. The RE-AIM framework was used to guide implementation outcomes. Differences in symptom trajectories and clinical outcomes between groups were tested using generalized estimating equations. RESULTS: We screened 388 patients of whom 250 were enrolled (acceptance rate: 64.4%), with 564 assessments being completed. The sample consisted of non-Hispanic White (NHW, 42.4%), Hispanic/Latinx (H/L, 30.8%), and non-Hispanic Asian (20.4%), with one (21.6%) of five participants preferring speaking Spanish. Compared with NHW, H/L participants had greater odds of reporting mild to severe pain interference (odds ratio [OR], 1.91 [95% CI, 1.18 to 3.08]; P = .008) and nausea and vomiting (OR, 2.08 [95% CI, 1.21 to 3.58]; P = .008), and higher rates of urgent care utilization (OR, 1.92 [95% CI, 1.04 to 3.61]; P = .04) within 30 days. Nausea and vomiting (n = 131, 23.2%), pain (n = 91, 16.1%), and fatigue (n = 72, 12.8%) were most likely to be intervened, with 90% of the participants expressing satisfaction across all visits. CONCLUSION: Our multilevel ePRO-driven intervention led by oncology pharmacists helps facilitate symptom assessments and management and potentially reduce health disparities among REM.
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Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with increased myocardial stiffness and cardiac filling abnormalities. Prior studies implicated increased α-tubulin detyrosination, which is catalyzed by the vasohibin enzymes, as a contributor to increased stabilization of the cardiomyocyte microtubule network (MTN) and stiffness in failing human hearts. We explored whether increased MTN detyrosination contributed to impaired diastolic function in the ZSF1 obese rat model of HFpEF and designed a small-molecule vasohibin inhibitor to ablate MTN detyrosination in vivo. Compared with ZSF1 lean and Wistar Kyoto rats, obese rats exhibited increased tubulin detyrosination concomitant with diastolic dysfunction, left atrial enlargement, and cardiac hypertrophy with a preserved left ventricle ejection fraction, consistent with an HFpEF phenotype. Ex vivo myocardial phenotyping assessed cardiomyocyte mechanics and contractility. Vasohibin inhibitor treatment of isolated cardiomyocytes from obese rats resulted in reduced stiffness and faster relaxation. Acute in vivo treatment with vasohibin inhibitor improved diastolic relaxation in ZSF1 obese rats compared with ZSF1 lean and Wistar Kyoto rats. Vasohibin inhibition also improved relaxation in isolated human cardiomyocytes from both failing and nonfailing hearts. Our data suggest the therapeutic potential for vasohibin inhibition to reduce myocardial stiffness and improve relaxation in HFpEF.
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Modelos Animales de Enfermedad , Insuficiencia Cardíaca , Miocitos Cardíacos , Volumen Sistólico , Animales , Humanos , Masculino , Ratas , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Diástole/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/patología , Miocardio/patología , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Ratas Endogámicas WKY , Volumen Sistólico/efectos de los fármacos , Tubulina (Proteína)/metabolismoRESUMEN
To evaluate how breakthrough rotavirus disease contributes to transmission, we examined the impact of rotavirus vaccination on fecal shedding and duration of illness. We used multivariable linear regression to analyze rotavirus quantity by RT-qPCR and duration among 184 episodes of rotavirus diarrhea positive by ELISA in the PROVIDE study. Vaccinated children had less fecal viral shedding compared to unvaccinated children (mean difference = -0.59 log copies per gram of stool; 95% confidence interval [CI], -.99 to -.19). Duration of illness was on average 0.47 days (95% CI, -.23 to 1.17 days) shorter among vaccinated children. Rotarix vaccination reduces shedding burden among breakthrough cases of rotavirus gastroenteritis. Clinical Trials Registration . NCT01375647.
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Heces , Infecciones por Rotavirus , Vacunas contra Rotavirus , Rotavirus , Vacunas Atenuadas , Esparcimiento de Virus , Humanos , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/inmunología , Infecciones por Rotavirus/prevención & control , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/virología , Lactante , Bangladesh/epidemiología , Rotavirus/inmunología , Heces/virología , Femenino , Masculino , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Gastroenteritis/virología , Gastroenteritis/prevención & control , Gastroenteritis/epidemiología , Vacunación , Diarrea/virología , Diarrea/prevención & control , Diarrea/epidemiología , Administración OralRESUMEN
BACKGROUND: There is a lack of uniformity across hospitals in applying inpatient versus observation status for short-stay (<48 h) pediatric hospitalizations, with negative financial implications associated with observation. Children with medical complexity (CMC) represent a growing population and incur high costs of care. The financial implications of inpatient and observation status for CMC have not been studied. OBJECTIVES: To compare costs and reimbursement for short-stay hospitalizations for CMC by inpatient and observation status, overall and stratified by payor. METHODS: We performed a cohort study of short-stay hospitalizations for CMC from 2016 to 2021 at 10 children's hospitals reporting reimbursement in the Pediatric Health Information System and Revenue Management Program. The primary outcome was the cost coverage ratio (CCR), defined as an encounter's reimbursement divided by the estimated cost. RESULTS: There were 89,282 encounters included. The median costs per encounter were similar across observation ($5206, IQR $3604-$7484) and inpatient ($6547, IQR $4725-$9349) encounters. For government payors, the median CCR was 0.6 (IQR 0.2-0.9) for observation encounters and 1.2 (IQR 0.8-1.9) for inpatient. For nongovernment payors, the median CCR was 1.6 (IQR 1.3-1.9) for observation and 1.6 (IQR 1.4-2) for inpatient. Government reimbursement was associated with increased risk for financial loss (OR 13.91, 95% CI 7.23, 26.77) and with a median net loss of $985,952 (IQR $389,871-$1,700,041) per hospital annually for observation encounters. CONCLUSIONS: Government-paid observation encounters for CMC are associated with significant financial loss at children's hospitals. This reimbursement model may pose a threat to children's hospitals' ability to care for CMC.
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PURPOSE: To describe the impact of an inpatient clinical oncology pharmacy technician program. METHODS: A retrospective study was conducted to observe outcomes in patients discharged from the hematology/oncology or bone marrow transplant (BMT) units at Indiana University Health in the year before (April 1, 2016-March 31, 2017) compared with the year after (April 1, 2018-March 31, 2019) the implementation of expanded technician services. The technician performed admission medication histories and ensured access to discharge medications. RESULTS: There were 1,169 and 1,112 encounters included in the pre- and post-technician cohorts. The median age was lower (54 v 61 years; P < .001), and there was a higher percentage of male patients (62% v 52.3%; P < .001) in the pre- compared with post-technician cohort. There were a higher percentage of oncology (36.4% v 31%; P = .007) and no difference in hematology (37.4% v 40.2%; P = .17) nor BMT encounters (26.3% v 28.8%; P = .18) in the pre- compared with post-technician cohort. The discharge prescription capture rate increased (42.7% v 78.5%; P < .001) from the pre- to post-technician cohort, resulting in a 34.2% increase ($314,639.46 in US dollars [USD]-$422,129.20 USD) in retail pharmacy revenue. More admission medication histories were completed by pharmacy staff (64.4% v 91.9%; P < .001), and there was an increase in the Hospital Consumer Assessment of Healthcare Providers and Systems-derived patient satisfaction results for both hematology/oncology (79% v 88%; P < .001) and BMT units (77% v 84%; P = .02) in the pre- compared with post-technician cohort. There was no difference in rates of unplanned readmissions (16.4% v 18.2%; P = .69) in the pre- compared with post-technician cohort. CONCLUSION: The overall capture rate of discharge prescriptions, revenue for the retail pharmacy, and patient satisfaction scores significantly increased after the implementation of expanded, inpatient clinical pharmacy technician services.
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BACKGROUND: To evaluate the predictive value of individual components of the R.E.N.A.L scoring system for Laparoscopic (LPN) and Robotic Partial Nephrectomy (RPN). METHODS: Patients that had undergone a Laparoscopic (LPN) or Robotic Partial Nephrectomy (RPN) between 2018 and 2023 were reviewed. Our data collection included Race, Ethnicity, Age, BMI, R.E.N.A.L nephrometry score, and complications. Cases that achieved trifecta outcomes were designated as "Group A" and cases that did not achieve trifecta were "Group B". All the data were collected using REDCap database. RESULTS: A total of 111 cases were included, Group A consisted of 82% of all cases, whereas Group B 18%. Radius score demonstrated significant distinction concerning trifecta attainment and was the most predictive component of the 5 scoring metrics of the nephrometry system. In a subgroup analysis, R-score of 3 or a renal mass measuring ≥ 7 cm, was a significant independent negative predictor for trifecta outcomes, as well as tumor size at presentation. CONCLUSION: Renal nephrometry score is predictive of trifecta outcomes for patients undergoing laparoscopic or robotic partial nephrectomy. Radius of mass was the most effective predictive component of the nephrometry score for trifecta prediction.
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Neoplasias Renales , Laparoscopía , Nefrectomía , Procedimientos Quirúrgicos Robotizados , Humanos , Nefrectomía/métodos , Laparoscopía/métodos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Resultado del Tratamiento , Anciano , Estudios Retrospectivos , Valor Predictivo de las PruebasRESUMEN
Engineered sex ratio distorters (SRDs) have been proposed as a powerful component of genetic control strategies designed to suppress harmful insect pests. Two types of CRISPR-based SRD mechanisms have been proposed: X-shredding, which eliminates X-bearing sperm, and X-poisoning, which eliminates females inheriting disrupted X-chromosomes. These differences can have a profound impact on the population dynamics of SRDs when linked to the Y-chromosome: an X-shredder is invasive, constituting a classical meiotic Y-drive, whereas X-poisoning is self-limiting, unable to invade but also insulated from selection. Here, we establish X-poisoning strains in the malaria vector Anopheles gambiae targeting three X-linked genes during spermatogenesis, resulting in male bias. We find that sex distortion is primarily driven by a loss of X-bearing sperm, with limited evidence for postzygotic lethality of female progeny. By leveraging a Drosophila melanogaster model, we show unambiguously that engineered SRD traits can operate differently in these two insects. Unlike X-shredding, X-poisoning could theoretically operate at early stages of spermatogenesis. We therefore explore premeiotic Cas9 expression to target the mosquito X-chromosome. We find that, by pre-empting the onset of meiotic sex chromosome inactivation, this approach may enable the development of Y-linked SRDs if mutagenesis of spermatogenesis-essential genes is functionally balanced.
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Anopheles , Drosophila melanogaster , Tecnología de Genética Dirigida , Razón de Masculinidad , Espermatogénesis , Cromosoma X , Animales , Masculino , Femenino , Anopheles/genética , Cromosoma X/genética , Drosophila melanogaster/genética , Tecnología de Genética Dirigida/métodos , Espermatogénesis/genética , Mosquitos Vectores/genética , Genes Ligados a X , Sistemas CRISPR-Cas , Espermatozoides/metabolismo , Animales Modificados GenéticamenteRESUMEN
The role of eculizumab in treating Shiga-toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) patients with neurological involvement remains unclear. We describe two distinctly different STEC-HUS patients with neurologic involvement successfully managed with eculizumab, and perform a literature review of all published cases. Both patients had complete resolution of neurological symptoms after initiation of eculizumab. Eighty patients with STEC-HUS treated with eculizumab were identified in the literature, 68.7% had complete resolution of neurological symptoms. Based on our experience and literature review, three prevailing themes were noted: 1) Early eculizumab administration optimized neurological outcomes, 2) Symptom resolution may not be immediate, neurological symptoms may initially worsen before improvement, and 3) Plasma exchange yielded no benefit. Early administration of eculizumab may reverse neurotoxicity in patients with STEC-HUS.
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Fungi harbor a vast diversity of mobile genetic elements (MGEs). Recently, novel fungal MGEs, tentatively referred to as 'ambiviruses,' were described. 'Ambiviruses' have single-stranded RNA genomes of about 4-5 kb in length that contain at least two open reading frames (ORFs) in non-overlapping ambisense orientation. Both ORFs are conserved among all currently known 'ambiviruses,' and one of them encodes a distinct viral RNA-directed RNA polymerase (RdRP), the hallmark gene of ribovirian kingdom Orthornavirae. However, 'ambivirus' genomes are circular and predicted to replicate via a rolling-circle mechanism. Their genomes are also predicted to form rod-like structures and contain ribozymes in various combinations in both sense and antisense orientations-features reminiscent of viroids, virusoids, ribozyvirian kolmiovirids, and yet-unclassified MGEs (such as 'epsilonviruses,' 'zetaviruses,' and some 'obelisks'). As a first step toward the formal classification of 'ambiviruses,' the International Committee on Taxonomy of Viruses (ICTV) recently approved the establishment of a novel ribovirian phylum, Ambiviricota, to accommodate an initial set of 20 members with well-annotated genome sequences.
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Genoma Viral , Sistemas de Lectura Abierta , Viroides , Viroides/genética , Viroides/clasificación , Filogenia , ARN Viral/genética , Virus ARN/genética , Virus ARN/clasificación , Hongos/genética , Hongos/virología , ARN Polimerasa Dependiente del ARN/genética , Virus Fúngicos/genética , Virus Fúngicos/clasificación , Virus Fúngicos/aislamiento & purificaciónRESUMEN
Background: Obesity is a well-established risk factor of renal cell carcinoma (RCC), however the impact of obesity on surgical outcomes for racial and ethnic minority patients with RCC is unclear. This study investigated whether a higher body mass index (BMI) or obesity (BMI ≥30 kg/m2) was associated with worse perioperative outcomes and if there were heterogeneous effects based on race, ethnicity, and neighborhood-level socioeconomic factor. Methods: In this single-center cross-sectional study, medical records of patients who underwent partial or radical nephrectomy between 2010 and 2022 were retrospectively reviewed. Logistic regression analysis was performed to assess associations of BMI and perioperative outcomes [ischemia time, estimated blood loss (EBL), and length of hospital stay]. Results: A total of 432 patients, including 49.8% non-Hispanic White (NHW), 35.0% Hispanic, and 6.9% American Indian (AI) patients, were included. Median [interquartile range (IQR)] BMI was 30.2 (26.3-35.2) kg/m2, and Hispanic (31.5) and AI (32.5) patients had higher median BMI than NHW (29.1) patients (P=0.006). Median ischemia time, EBL, and length of hospital stay were 18.5 (IQR, 15.0-22.4) minutes, 150 (IQR, 75.0-300.0) mL, and 3 (IQR, 2-5) days. BMI ≥35 kg/m2 was associated with a longer ischemia time [>18.5 minutes; odds ratio (OR), 5.17; 95% confidence interval (CI): 1.81-14.76; P=0.002], and the association was stronger in NHW than Hispanic patients (BMI continuous OR, 1.13; 95% CI: 1.04-1.22; P=0.004 in NHW and OR, 1.07; 95% CI: 0.98-1.17; P=0.12 in Hispanics). Class I and II/III obese patients had over two-fold increased odds of a larger EBL (>150 mL) than patients with normal weight (OR, 2.17; 95% CI: 1.03-4.59; P=0.04 for class I and OR, 2.24; 95% CI: 1.04-4.84; P=0.04 for class II/III obese patients). This association was stronger in patients from neighborhoods with high social deprivation index (SDI) and in NHW patients (BMI ≥30 vs. <30 kg/m2, OR, 3.53; 95% CI: 1.57-7.97; P=0.002 in high SDI neighborhoods and OR, 2.38; 95% CI: 1.10-5.14; P=0.03 in NHW). BMI was not associated with a longer hospital stay. Conclusions: In this study, obesity increased likelihood of worse perioperative outcomes, and the associations varied based on race and ethnicity and neighborhood-level socioeconomic factors.
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BACKGROUND: As global travel resumed in coronavirus disease 2019 (COVID-19) endemicity, the potential of aircraft wastewater monitoring to provide early warning of disease trends for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and other infectious diseases, particularly at international air travel hubs, was recognized. We therefore assessed and compared the feasibility of testing wastewater from inbound aircraft and airport terminals for 18 pathogens including SARS-CoV-2 in Singapore, a popular travel hub in Asia. METHODS: Wastewater samples collected from inbound medium- and long-haul flights and airport terminals were tested for SARS-CoV-2. Next Generation Sequencing was carried out on positive samples to identify SARS-CoV-2 variants. Airport and aircraft samples were further tested for 17 other pathogens through quantitative reverse transcription polymerase chain reaction. RESULTS: The proportion of SARS-CoV-2-positive samples and the average virus load was higher for wastewater samples from aircraft as compared with airport terminals. Cross-correlation analyses indicated that viral load trends from airport wastewater led local COVID-19 case trends by 2-5 days. A total of 10 variants (44 sub-lineages) were successfully identified from aircraft wastewater and airport terminals, and four variants of interest and one variant under monitoring were detected in aircraft and airport wastewater 18-31 days prior to detection in local clinical cases. The detection of five respiratory and four enteric viruses in aircraft wastewater samples further underscores the potential to expand aircraft wastewater to monitoring pathogens beyond SARS-CoV-2. CONCLUSION: Our findings demonstrate the feasibility of aircraft wastewater testing for monitoring infectious diseases threats, potentially detecting signals before clinical cases are reported. The triangulation of similar datapoints from aircraft wastewater of international travel nodes could therefore serve as a useful early warning system for global health threats.
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Aeronaves , Aeropuertos , COVID-19 , SARS-CoV-2 , Aguas Residuales , Humanos , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , Aguas Residuales/virología , COVID-19/diagnóstico , COVID-19/epidemiología , Singapur/epidemiología , Carga ViralRESUMEN
Ribonucleoside modifications comprising the epitranscriptome are present in all organisms and all forms of RNA, including mRNA, rRNA and tRNA, the three major RNA components of the translational machinery. Of these, tRNA is the most heavily modified and the tRNA epitranscriptome has the greatest diversity of modifications. In addition to their roles in tRNA biogenesis, quality control, structure, cleavage, and codon recognition, tRNA modifications have been shown to regulate gene expression post-transcriptionally in prokaryotes and eukaryotes, including humans. However, studies investigating the impact of tRNA modifications on gene expression in the malaria parasite Plasmodium falciparum are currently scarce. Current evidence shows that the parasite has a limited capacity for transcriptional control, which points to a heavier reliance on strategies for posttranscriptional regulation such as tRNA epitranscriptome reprogramming. This review addresses the known functions of tRNA modifications in the biology of P. falciparum while highlighting the potential therapeutic opportunities and the value of using P. falciparum as a model organism for addressing several open questions related to the tRNA epitranscriptome.
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Objective: The objective of this study was to examine the impact of the introduction of the Universal Anaesthesia Machine (UAM), a device designed for use in clinical environments with limited clinical perioperative resources, on the choice of general anesthesia technique and safe anesthesia practice in a tertiary-care hospital in Sierra Leone. Methods: We introduced an anesthesia machine (UAM) into Connaught Hospital, Freetown, Sierra Leone. We conducted a prospective observational study of anesthesia practice and an examination of perioperative clinical parameters among surgical patients at the hospital to determine the usability of the device, its impact on anesthesia capacity, and changes in general anesthesia technique. Findings: We observed a shift from the use of ketamine total intravenous anesthesia to inhalational anesthesia. This shift was most demonstrable in anesthesia care for appendectomies and surgical wound management. In 10 of 17 power outages that occurred during inhalational general anesthesia, anesthesia delivery was uninterrupted because inhalational anesthesia was being delivered with the UAM. Conclusion: Anesthesia technologies tailored to overcome austere environmental conditions can support the delivery of safe anesthesia care while maintaining fidelity to recommended international anesthesia practice standards.
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Androgen Receptor (AR) activity in prostate stroma is required to maintain prostate homeostasis. This is mediated through androgen-dependent induction and secretion of morphogenic factors that drive epithelial cell differentiation. However, stromal AR expression is lost in aggressive prostate cancer. The mechanisms leading to stromal AR loss and morphogen production are unknown. We identified TGFß1 and TNFα as tumor-secreted factors capable of suppressing AR mRNA and protein expression in prostate stromal fibroblasts. Pharmacological and RNAi approaches identified NF-κB as the major signaling pathway involved in suppressing AR expression by TNFα. In addition, p38α- and p38δ-MAPK were identified as suppressors of AR expression independent of TNFα. Two regions of the AR promoter were responsible for AR suppression through TNFα. FGF10 and Wnt16 were identified as androgen-induced morphogens, whose expression was lost upon TNFα treatment and enhanced upon p38-MAPK inhibition. Wnt16, through non-canonical Jnk signaling, was required for prostate basal epithelial cell survival. These findings indicate that stromal AR loss is mediated by secreted factors within the TME. We identified TNFα/TGFß as two possible factors, with TNFα mediating its effects through NF-κB or p38-MAPK to suppress AR mRNA transcription. This leads to loss of androgen-regulated stromal morphogens necessary to maintain normal epithelial homeostasis.
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FN-kappa B , Neoplasias de la Próstata , Receptores Androgénicos , Células del Estroma , Proteínas Quinasas p38 Activadas por Mitógenos , Masculino , Humanos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , FN-kappa B/metabolismo , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Células del Estroma/metabolismo , Células del Estroma/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Factor de Necrosis Tumoral alfa/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Proteínas Wnt/metabolismo , Proteínas Wnt/genética , Transducción de Señal , Próstata/patología , Próstata/metabolismoRESUMEN
Patients undergoing allogenic hematopoietic stem cell transplantation (HSCT) are at an increased risk of mortality due to transplantation-related complications in the first year post-transplantation, owing in part to the profound immune dysregulation with T cell and B cell lymphopenia and functional impairment. Although several large studies have reported higher mortality rates from Coronavirus disease 2019 (COVID-19) in HSCT recipients, to date no study has focused on the impact of early COVID-19 infection on immune reconstitution post-transplantation and the correlation with transplantation outcomes. We retrospectively analyzed 61 consecutive adult patients who underwent their first allogeneic HSCT at our institution. Thirteen patients (21.3%) experienced early COVID-19 infection, with a median time to diagnosis of 100 days post-transplantation. In multivariable analysis, patients with early COVID-19 infection had significantly worse overall survival (adjusted hazard ratio [aHR], 4.06; 95% confidence interval [CI], 1.26 to 13.05; P = .019) and progression-free survival (aHR, 6.68; 95% CI, 2.11 to 21.11; P = .001). This was attributed mainly to higher nonrelapse mortality (NRM) among early COVID-19 patients (P = .042). Allogeneic HSCT recipients with early COVID-19 infection had significant delays in absolute lymphocyte count (95% CI, -703.69 to -56.79; P = .021), CD3+CD4+ cell (95% CI, -105.35 to -11.59; P = .042), CD3+CD8+ cell (95% CI, -324.55 to -57.13; P = .038), and CD3-CD56+ cell (95% CI, -193.51 to -47.31; P = .014) recovery compared to those without early COVID-19 infection. Our findings suggest that patients with early COVID-19 infection after allogeneic HSCT have higher NRM and worse survival, at least in part due to impaired immune reconstitution post-transplantation.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune , SARS-CoV-2 , Trasplante Homólogo , Humanos , COVID-19/mortalidad , COVID-19/inmunología , COVID-19/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , SARS-CoV-2/inmunología , Trasplante Homólogo/efectos adversos , AncianoRESUMEN
BACKGROUND: Colonoscopy is a diagnostic and therapeutic procedure that reduces colorectal cancer incidence and mortality but requires adequate bowel cleansing for high-quality examination. Past studies have suggested cirrhosis as a risk factor for worse bowel preparation. METHODS: We carried out a match-controlled retrospective study evaluating patients with and without cirrhosis who underwent outpatient screening colonoscopies to assess the effect of cirrhosis and portal hypertension complications on preparation quality and endoscopic measures. We also did a subgroup analysis excluding patients with obesity. RESULTS: We examined 1464 patients with cirrhosis and matched controls. Cirrhotic patients had lower mean Boston Bowel Preparation Scale (BBPS) scores and slower cecal intubation times. We found a single point increase in the Model for End-stage Liver Disease (MELD) score, as well as ascites, hepatic encephalopathy, and variceal hemorrhage were all associated with a longer cecal intubation time. Subgroup analysis excluding patients with obesity again found a significantly lower BBPS score and longer cecal intubation time while also finding a 24% drop in polyp detection. CONCLUSIONS: Patients with cirrhosis have worse BBPS scores and longer cecal intubation times. Nonobese cirrhotic patients additionally have a lower polyp detection rate. Portal hypertension complications were associated with worsened preparation quality and longer cecal intubation times. Each incremental increase in MELD score lengthened cecal intubation time. These findings support a more aggressive bowel preparation strategy for patients with cirrhosis, especially patients with severe disease or portal hypertension complications.
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Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening, hyperinflammatory syndrome for which etoposide-based regimens have historically been the standard of care. Recent reports have described positive outcomes with the utilization of ruxolitinib or anakinra although these studies are often limited to small samples. Objectives: We aimed to compare the efficacy of ruxolitinib, anakinra, and etoposide-based therapies for the management of HLH in adult patients. Design: We performed a population-based, multicenter, retrospective cohort study utilizing the TriNetX Networks database. Methods: Adult patients (⩾18 years) diagnosed with HLH who received first-line treatment with ruxolitinib, anakinra, or etoposide between 2008 and 2023 were analyzed. The primary endpoint was overall survival (OS) at 1 year. A 1:1 propensity-score matching analysis was utilized. Results: Anakinra (p = 0.020) but not ruxolitinib (p = 0.19) resulted in a significantly higher 1-year OS when compared with etoposide-based therapies. Conclusions: Anakinra is effective for the management of adult patients with HLH.